Throughout this application, various publications are referenced by number. Full citations for these publications may be found listed at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
The pain of Alzheimer""s disease results directly from the memory loss and cognitive deficits suffered by the patient. These eventually result in the patient""s loss of identity, autonomy, and freedom. As a step toward curing this disease, alleviating its symptoms, or retarding its progression, it would be desirable to develop a transgenic animal model exhibiting the main debilitating phenotype of Alzheimer""s disease, that is, memory loss, expressed concomitantly with the neuropathological correlates of Alzheimer""s disease, for example, beta-amyloid accumulation, increased glial reactivity, and hippocampal cell loss.
It is estimated that over 5% of the U.S. population over 65 and over 15% of the U.S. population over 85 are beset with some form of Alzheimer""s disease (Cross, A. J., Eur J Pharmacol (1982) 82:77-80; Terry, R. D., et al., Ann Neurol (1983) 14:497-506). It is believed that the principal cause for confinement of the elderly in long term care facilities is due to this disease, and approximately 65% of those dying in skilled nursing facilities suffer from it.
Certain facts about the biochemical and metabolic phenomena associated with the presence of Alzheimer""s disease are known. Two morphological and histopathological changes noted in Alzheimer""s disease brains are neurofibrillary tangles (NFT) and amyloid deposits. Intraneuronal neurofibrillary tangles are present in other degenerative diseases as well, but the presence of amyloid deposits both in the interneuronal spaces (neuritic plaques) and in the surrounding microvasculature (vascular plaques) seems to be characteristic of Alzheimer""s. Of these, the neuritic plaques seem to be the most prevalent (Price, D. L., et al., Drug Development Research (1985) 5:59-68). Plaques are also seen in the brains of aged Down""s Syndrome patients who develop Alzheimer""s disease.
The present invention provides for a transgenic non-human transgenic animal whose cells contain a recombinant DNA sequence comprising: (a) a nerve tissue specific promoter operatively linked to a DNA sequence which encodes human receptor for advanced glycation endproducts (RAGE), and (b) a nerve tissue specific promoter operatively linked to a DNA sequence encoding a mutant human amyloid precursor protein hAPP695, hAPP751 and hAPP770 bearing mutations linked to familial Alzheimer""s disease in humans, wherein said non-human transgenic animal exhibits at least one phenotype from the group consisting of: increased expression of M-CSF gene in cerebral cortex; increased expression of IL-6 gene in cerebral cortex; increased neuronal stress; increased neurotoxicity; neuron loss; increased level of activated form of caspase 3 in brain; and increased level of phosphorylated tau protein in brain.